Project Summary: Deep brain stimulation (DBS) of basal ganglia is a well-established therapy for a variety of movement disorders, such as Parkinson's disease (PD) and essential tremor. In addition, it is also an emerging therapy for several psychiatric and neurological conditions, including epilepsy, major depression and obsessive- compulsive disorder (OCD). Despite its clinical success, there is a limited understanding of the neural mechanism behind DBS. Typical DBS system consists of a pulse generator, which deliveries the stimulation pulses via an implanted metal electrode. It is possible that DBS exerts is therapeutic effect through several different mechanisms including: (1) directly regulating neural firing at target nucleus; (2) activating nearby neuronal axons; (3) influencing passing long-range projection axons by activating antidromic and orthodromic action potentials. Because current DBS electrodes excite a large volume of neural tissue, it has been difficult to precisely determine which of these targets and mechanisms are responsible for the therapeutic effects of DBS. It is therefore critical to develop next generation DBS technology that enables selective targeting of different populations of neural structures, ideally with single neuron and single axon fiber precision. In addition, it would be beneficial to develop massively parallel DBS electrode arrays (10,000+ electrodes) to delivery different spatiotemporal patterns of activity that can be optimized for therapeutic efficacy. Recent methodological advances in material science and engineering now make such a device possible. This proposal describes a high-density, massively parallel single cell and single axon level stimulation device based on bundled microwires (BMWs): tens of thousands of metal-in-glass wires of less than 30 micrometers outer diameter. The approach will be revolutionary for neurophysiology, allowing break-through experiments both in movement disorders and fundamental understanding of neural circuit behavior. Here we propose: 1) To develop and characterize a BMW stimulation array and demonstrate its efficacy in acute brain slices and in vivo. 2) To couple the BMW array with modern semiconductor technology, demonstrating that driver circuit of a commercially available micro-display chip is capable of injecting patterned stimulation current through the BMW. We will validate the performance in brain slices and in vivo to test if different patterns of electrical stimulation reliably generate corresponding activity patterns in the brain slice and in vivo. Together, this proposal will bring neuroscience and engineering together to create the highest density electrophysiological stimulation interface ever made, and provide proof of principle demonstrations through the combined approaches of microwire stimulation, 2-photon functional imaging and classical electrophysiology. These microwire arrays would be a powerful tool, which would not only offer substantial clinical benefits for movement disorders, such as PD, but also provide mechanistic insights for DBS. 1